1. Field of the Invention
The present invention relates to a process for preparing sodium or potassium salts of 4-hydroxy-2-oxo-2,5-dihydrofuran-3-carboxylic esters proceeding from malonic esters.
2. Description of Related Art
The preparation of hydroxy-2-oxo-2,5-dihydrofuran-3-carboxylic esters, the corresponding tautomers or the alkali metal salts thereof, and also the use thereof as a component in the synthesis of biologically active compounds, is known (WO 2011/018180, WO 2009/036899, J. Chem. Soc., Perkin Trans. 1, 1985, pages 1567 to 1576, Berichte der Deutschen Chemischen Gesellschaft (1911), 44, 1759-1765). However, the known processes have disadvantages as described hereinafter.
WO 2011/018180 describes the preparation of hydroxy-2-oxo-2,5-dihydrofuran-3-carboxylic ester and proceeds from malonic ester in the synthesis described therein. The latter is reacted with a haloacetyl chloride compound in the presence of a base (see reaction scheme 1). After addition of water, the desired 4-hydroxy-2-oxo-2,5-dihydrofuran-3-carboxylic ester is obtained. The base is selected so as to be capable of deprotinating the malonic ester, as a result of which the enolate of the malonic ester is formed, which is then acetylated by the haloacetyl chloride compound. Suitable bases are especially alkoxides of the general formula M(ORa)b, in which M is Na+, K+, Mg2+, b is 1 or 2 and Ra is methyl or ethyl. Sodium methoxide is specified as preferred. On completion of ring closure, the desired product is obtained together with an inorganic salt which is obtained as a by-product (e.g. NaCl if a sodium alkoxide is used as the base).

The removal of the inorganic salt from the reaction mixture, especially when it is NaCl, is achievable only through a very high level of technical complexity, if at all, since the compounds of the formula (P-I) and (P-I′) are of very good water solubility. Distillation is impossible since the compounds of the formula (P-I) and (P-I′) decompose at relatively high temperatures with release of CO2. The inorganic salt is therefore not removed. It is introduced into the subsequent reaction and can only be removed on completion of further reaction of the compounds of the formula (P-I) and/or (P-I′).
WO 2009/036899 describes the synthesis of salts of 4-hydroxy-2-oxo-2,5-dihydrofuran-3-carboxylic esters, which proceeds from malonic ester potassium salt and in which the corresponding salt of the 4-hydroxy-2-oxo-2,5-dihydrofuran-3-carboxylic ester is prepared using chloroacetic ester and an alkoxide base, e.g. sodium methoxide (see reaction scheme 2). This reaction does not give rise to any inorganic salts which have to be carried onward, but the reaction uses dimethylformamide or dimethylacetamide as a solvent, which are firstly expensive and secondly difficult to remove and recoverable only with difficulty.

Step 1 of the aforementioned reaction is an esterification in which potassium chloride is obtained as a by-product and subsequently has to be separated from the reaction mixture. In step 2, the ring closure to give the desired compound (Q-II) takes place, and a transesterification may occur therein, which results in isolation of a compound of the formula (Q-II′). The transesterification in step 2 can be suppressed by using alkoxides which contain sterically demanding Rf radicals (for example a tert-butyl alkoxide). Compounds of the formula (Q-IV) are solids, are commercially available or can be prepared by known processes (cf. J. Am. Chem. Soc. 1944, No. 66, page 1286, EP-A-950653, WO 2008/150487).
The reaction is disadvantageous for industrial scale use since it proceeds from expensive malonic ester potassium salts of the formula (Q-IV) present in solid form. In the case of industrial scale preparation, the use of solids as starting materials is fundamentally undesirable since the technical handling of such solids is difficult and there are often changes of solvents, which leads overall to considerable technical complexity in the performance of the reaction.